Benzoylecgonine, ecgonine and ecgonidine are known metabolites of cocaine (see, for example, S. M. Roberts et al., "An Assay for Cocaethylene and Other Cocaine Metabolites in Liver Using High-Performance Liquid Chromatography", Anal. Biochem., 202, pp. 256-61 (1992); D. T. Chia and J. A. Gere, "Rapid Drug Screening Using Toxi-Lab Extraction Followed by Capillary Gas Chromatography/Mass Spectroscopy", Clin. Biochem., 20, pp. 303-06 (1987)). Routes for their preparation have been established (see, for example, A. H. Lewin et al., "2.beta.-Substituted Analogues of Cocaine. Synthesis and Binding to the Cocaine Receptor", J. Med. Chem., 35, pp. 135-40 (1992); M. R. Bell and S. Archer, "L(+)-2-Tropinone", J. Amer. Chem. Soc., 82, pp. 4642-44 (1960)).
We have demonstrated the pharmaceutical efficacy of benzoylecgonine and ecgonine in the treatment of rheumatoid arthritis and osteoarthritis (see, for example, U.S. Pat. Nos. 4,469,700, 4,512,996 and 4,556,663). Unfortunately, the original promise of these compounds has not been fully realized. Due to their low rate of absorption into the blood stream and their low solubility in solution, the effective dose must be relatively high and certain modes of administration (such as topical administration) are less practical. In addition, neither benzoylecgonine nor ecgonine cross the blood/brain barrier. Therefore, these compounds are not effective in treating disorders of the central nervous system.
All the above-mentioned restrictions limit the number of potential uses for benzoylecgonine, ecgonine and ecgonidine. Therefore, a need exists for easily synthesized, stable derivatives of these compounds which will be more easily absorbed into the bloodstream without adverse side effects, while maintaining a high level of therapeutic efficacy.